Project Summary/Abstract Alzheimer's disease (AD) is one of the most persistent and devastating ailment of old age. Besides the deposition of ?-amyloid plaques and accumulation of neurofibrillary tangles, AD brains are marked by prominent neuroinflammatory responses, which plays a crucial role in disease pathogenesis. Although aging is known to profoundly influence tissue homeostasis, how age-induced brain inflammation specifically contributes to the progression of AD remains elusive. The cytokine family type I interferon (IFN) is a major innate immune mediator produced in response to microbial infections. We have detected elevated signals of IFN pathway activation in the brains of normal aging mice as well as APP transgenic and knock-in animals expressing human amyloid beta (A?). Previously by manipulating the generation of amyloid, we established that innate immune cells readily produce IFN upon exposure to certain form of amyloid via activating nucleic acid-sensing innate immune receptors in vitro and in vivo, suggesting that amyloid aggregation may serve as endogenous stimulus to chronically activate IFN pathway in AD. Consistent with these observations, a panel of IFN pathway genes were expressed at increased levels in an archived human AD dataset. At this time, the functional significance of IFN pathway activation in the context of AD-related neuroinflammation is unclear. Separately, aging-associated IFN activation predominantly affect choroid plexus (CP), a membrane structure that interfaces the cerebrospinal space and the blood brain capillaries. How this element of IFN signaling affects AD pathogenesis has not been modeled so far. Based on these intriguing observations, we hypothesize that IFN pathway critically participates in normal brain aging and, further under protein homeostatic stress, promotes AD pathogenesis. This application seeks the answers to the urgent scientific question how a novel arm of neuroinflammation contribute to AD from both brain parenchyma and neurovascular barrier. We propose three specific aims - 1: Map age-dependent activation of IFN pathway in normal aging and in response to A? pathology; 2: Define the functional significance of IFN pathway activation in A? pathology; and 3: Identify IFN-regulated molecular signatures central to AD pathogenesis in both mouse AD models and human patients. These studies are expected to generate unprecedented insights on how IFN pathway affects the pathogenesis of AD and reveal potential crosstalk between all major neuroinflammatory pathways, which may facilitate the identification of novel biomarkers and therapeutic targets.